This project was initiated to fill a void in our knowledge regarding the neurobiological substrates of the the adverse effects of chronic marijuana use on cognition in humans. It is well-known that both acute and chronic marijuana use in humans impairs short-term memory, reaction times, and general higher-order cognitive processing. These studies seek to utilize animal models to explore the effects of both acute and chronic exposure to the main psychoactive ingredient in marijuana, delta9-tetrahydrocannabinol (THC) on the neurophysiology of the hippocampus. One series of experiments involve repeated i.p. injections with THC for varying periods of time, followed by varying periods of withdrawal from the drug, and then evaluation of electrophysiological parameters in brain slices containing the rodent hippocampus. Results from these studies, published earlier this year, indicate that following a 1d withdrawal from a 7d treatment with THC, the drug was undetectable in hippocampus using LC-MS. However, the 7d exposure to THC produced tolerance to the inhibition of GABA, but not glutamate release by the cannabinoid agonist WIN55,212-2. Additionally, unlike controls, the hippocampal slices from the chronic THC animals did not demonstrate long-term potentiation (LTP), a cellular correlate of learning and memory. A single injection of THC was insufficient to block LTP, the LTP blockade persisted for 3d after the last THC injection, and it was prevented by pretreatment of the animals before each THC injection with the antagonist AM251 (2 mg/kg). Additional experiments now under way will examine the hypothesis that the CB1 cannabinoid receptor is necessary to permit normal cognition and learning and memory over the life span of an organism. For these studies, we are comparing the level of LTP in hippocampal brain slices obtained from CB1+/+ and -/- animals at various ages. In addition, we are defining the actions of acute THC exposure on individual neurons in hippocampal brain slices using whole-cell recordings. The majority of studies to date have utilized synthetic CB agonists to assess the role of CB1 receptors in modulating hippocampal synaptic function. By comparing the effects of THC to those of these synthetic agonists, we hope to identify putative molecular targets of THC that may help explain memory impairments in humans following chronic marijuana use. These experiments will also define the consequences of both acute and repeated THC exposure in the rodent hippocampus and will define the importance of the CB1 receptor in cognition throughout the lifespan of the mouse.